In recent years, it has been realized that phospholipases A2 (PLA2, EC 3.1.1.4) form a superfamily of intracellular and secreted enzymes, which all catalyze the hydrolysis of glycerophospholipids at the sn-2 position to release fatty acids and lysophospholipids (1-4). To date, 8 distinct mammalian secreted phospholipases A2 (sPLA2S) have been cloned and classified into groups I, II, V and X (2, 4-9). Although the biological role of each of these enzymes has not yet been clearly defined, mammalian sPLA2s have been implicated in various physiological and pathophysiological functions including lipid digestion, cell proliferation, neurosecretion, release of proinflammatory lipid mediators, antibacterial defence, cancer and inflammatory diseases (3, 4). The level of identity between the 8 mammalian sPLA2s can be as low as 23% (8), but they have in common a low molecular mass (14-17 kDa), the presence of several disulfides, a similar Ca2+-dependent catalytic mechanism, and a well conserved overall three-dimensional structure (10-13).
Numerous sPLA2s have also been described in venoms from both vertebrate and invertebrate animals such as snakes and bees (14, 15). Similar to mammalian sPLA2s, snake venom enzymes have been classified into groups I and II, and they all have a common catalytic mechanism and a very similar three-dimensional structure (1, 10-13). Snake venom sPLA2s are often neurotoxins or myotoxins, but can also promote physiological effects such as cell migration and cell proliferation (14, 16, 17). Using venom sPLA2s as ligands, different types of sPLA2 receptors have been identified (4). These receptors are likely to be involved in venom sPLA2 toxicity, and recent studies have suggested that mammalian sPLA2s can be the normal endogenous ligands (4, 18, 19). Invertebrate venom sPLA2s are also disulfide-rich proteins, but they have a primary structure distinct from mammalian and snake venom sPLA2s, and have been classified into groups III and IX (2, 4). They have been found in bee, scorpion, jellyfish and marine snail venoms (20-25), and the group III bee venom sPLA2 has been the best studied enzyme. This sPLA2 has been cloned (20) and determination of its three-dimensional structure (11) has revealed important differences with group I and II sPLA2s, although the catalytic site is similar to that of vertebrate sPLA2s (13). Interestingly, sPLA2s similar to the bee venom enzyme were discovered in lizard venom (26, 27), indicating that group III sPLA2s also exist in vertebrates, and thus may occur in mammals as well.